Phenetole

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Link to relevant study records

Reference

Reference 1

Endpoint:

two-generation reproductive toxicity

Remarks:

based on test type (migrated information)

Type of information:

migrated information: read-across based on grouping of substances (category approach)

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Qualifier:

according to guideline

Guideline:

other: estimated data

Principles of method if other than guideline:

Prediction using category approach; QSAR Toolbox 3.1; Read Across; 5 nearest analogues; Log Kow as descriptor

GLP compliance:

no

Limit test:

no

Species:

rat

Strain:

Wistar

Sex:

male/female

Route of administration:

dermal

Vehicle:

unchanged (no vehicle)

Details on exposure:

DIET PREPARATION
Feeded orally

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

8 weeks

Remarks:

Doses / Concentrations:
100, 300, 1000 mg/kg bw/d
Basis:

Control animals:

yes, concurrent vehicle

Parental animals: Observations and examinations:

CAGE SIDE OBSERVATIONS: Yes
DETAILED CLINICAL OBSERVATIONS: Yes
BODY WEIGHT: Yes
FOOD CONSUMPTION:
- Food consumption for each animal determined: Yes

Litter observations:

number and sex of pups (Sex ratio), stillbirths, live births, postnatal mortality, presence of gross anomalies, clinical symptoms, body weights

Postmortem examinations (parental animals):

HISTOPATHOLOGY / ORGAN WEIGHTS

Postmortem examinations (offspring):

SACRIFICE and GROSS NECROPSY

Reproductive indices:

Male/female mating index, Male/female fertility index, Gestation index, Live birth index, Postimplantation loss

Clinical signs:

no effects observed

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

no effects observed

Organ weight findings including organ / body weight ratios:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Other effects:

no effects observed

Reproductive function: oestrous cycle:

no effects observed

Reproductive function: sperm measures:

no effects observed

Reproductive performance:

no effects observed

Dose descriptor:

NOAEL

Remarks:

general systemic toxicity, Fertility, Developmental toxicity

Effect level:

1 360 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: see 'Remark'

Remarks on result:

other: Generation: P,F1 (migrated information)

Critical effects observed:

not specified

System:

other: not specified

Organ:

not specified

Treatment related:

not specified

Dose response relationship:

not specified

Relevant for humans:

not specified

Clinical signs:

no effects observed

Mortality / viability:

no mortality observed

Body weight and weight changes:

no effects observed

Sexual maturation:

no effects observed

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

no effects observed

Histopathological findings:

not examined

Remarks on result:

not measured/tested

Reproductive effects observed:

not specified

Treatment related:

not specified

Relation to other toxic effects:

not specified

Dose response relationship:

not specified

Relevant for humans:

not specified

The prediction was based on dataset comprised from the following descriptors: "NOAEL Fertility","NOAEL Developmental toxicity","NOAEL general systemic toxicity",NOAEL,"NOAEL general effects","NOAEL reproductive effects",LOAEL,"LOAEL reproductive effects","LOAEL general effects"
Estimation method: Takes average value from the 5 nearest neighbours
Domain  logical expression:Result: In Domain

((((("a" or "b" or "c" or "d" )  and ("e" and ( not "f") )  )  and (("g" or "h" or "i" or "j" )  and ("k" and ( not "l") )  )  and (("m" or "n" or "o" or "p" )  and ("q" and ( not "r") )  )  )  and ("s" and ( not "t") )  )  and ("u" and "v" )  )

Domain logical expression index: "a"

Referential boundary: The target chemical should be classified as Alkoxy AND Aryl AND Ether by Organic functional groups

Domain logical expression index: "b"

Referential boundary: The target chemical should be classified as Alkoxy AND Aryl AND Ether AND Overlapping groups by Organic functional groups (nested)

Domain logical expression index: "c"

Referential boundary: The target chemical should be classified as Aliphatic Carbon [CH] AND Aliphatic Carbon [-CH2-] AND Aliphatic Carbon [-CH3] AND Aromatic Carbon [C] AND Olefinic carbon [=CH- or =C<] AND Oxygen, one aromatic attach [-O-] by Organic functional groups (US EPA)

Domain logical expression index: "d"

Referential boundary: The target chemical should be classified as Alkylarylether AND Aromatic compound AND Ether by Organic functional groups, Norbert Haider (checkmol)

Domain logical expression index: "e"

Referential boundary: The target chemical should be classified as No alert found by DNA binding by OASIS v.1.1

Domain logical expression index: "f"

Referential boundary: The target chemical should be classified as Acylation OR Acylation >> Direct acyation involving a leaving group OR Acylation >> Direct acyation involving a leaving group >> Geminal Polyhaloalkanes OR Elimination (E2) OR Elimination (E2) >> E2 elimination reaction with epoxide formation OR Elimination (E2) >> E2 elimination reaction with epoxide formation >> Haloalcohols OR Michael addition OR Michael addition >> alpha, beta-unsaturated carabonyl compounds OR Michael addition >> alpha, beta-unsaturated carabonyl compounds >> Alpha, Beta-Unsaturated Aldehydes OR Michael addition >> alpha, beta-unsaturated carabonyl compounds >> Four- and Five-Membered Lactones OR Michael addition >> Quinone type compounds OR Michael addition >> Quinone type compounds >> Quinoneimine Derivatives OR Michael addition >> Quinone type compounds >> Quinones OR Nucleophilic addition OR Nucleophilic addition >> Nucleophilic addition reaction with cycloisomerization OR Nucleophilic addition >> Nucleophilic addition reaction with cycloisomerization >> Hydrazine Derivatives OR Radical OR Radical >> Free radical formation OR Radical >> Free radical formation >> Arenediazonium Salts OR Radical >> Generation of reactive oxygen species OR Radical >> Generation of reactive oxygen species >> Coumarins OR Radical >> Generation of reactive oxygen species >> Thiols OR Radical >> Radical decomposition OR Radical >> Radical decomposition >> Alkylnitrites OR Radical >> Radical mechanism by ROS formation OR Radical >> Radical mechanism by ROS formation >> Diazenes OR Radical >> Radical mechanism by ROS formation >> Geminal Polyhaloalkanes OR Radical >> Radical mechanism by ROS formation >> Hydrazine Derivatives OR Radical >> Radical mechanism by ROS formation >> Nitro Compounds OR Radical >> Radical mechanism by ROS formation >> Nitroso compounds OR Radical >> Radical mechanism by ROS formation >> Organic Peroxy Compounds OR Radical >> Radical mechanism by ROS formation >> Quinones OR Radical >> Radical mechanism by ROS formation >> Specific Imine and Thione Derivatives OR Radical >> ROS formation after GSH depletion OR Radical >> ROS formation after GSH depletion >> Aromatic and Heterocyclic Primary Amines OR Radical >> ROS formation after GSH depletion >> Haloalcohols OR Radical >> ROS formation after GSH depletion >> Quinoneimine Derivatives OR Schiff base fomers OR Schiff base fomers >> Direct acting Schiff base formers OR Schiff base fomers >> Direct acting Schiff base formers >> Alkylnitrites OR Schiff base fomers >> Direct acting Schiff base formers >> Alpha, Beta-Unsaturated Aldehydes OR Schiff base fomers >> Direct acting Schiff base formers >> Geminal Polyhaloalkanes OR Schiff base fomers >> Direct acting Schiff base formers >> Specific Acetate Esters OR Schiff base fomers >> Multi-step Shiff base formation OR Schiff base fomers >> Multi-step Shiff base formation >> Haloalkanes Containing Electron-Withdrawing Groups OR SN1 OR SN1 >> Carbenium ion formation OR SN1 >> Carbenium ion formation >> Alpha-Haloethers OR SN1 >> Carbenium ion formation >> Nitroso compounds OR SN1 >> Carbenium ion formation >> Polycyclic Aromatic Hydrocarbons OR SN1 >> Carbenium ion formation >> Specific Acetate Esters OR SN1 >> Glutathione-induced nitrenium ion formation OR SN1 >> Glutathione-induced nitrenium ion formation >> Nitroso compounds OR SN1 >> Nitrenium and/or Carbenium ion formation OR SN1 >> Nitrenium and/or Carbenium ion formation >> Urea Derivatives OR SN1 >> Nitrenium ion and/or Acyl ion formation OR SN1 >> Nitrenium ion and/or Acyl ion formation >> N-acyloxy-N-alkoxyamides OR SN1 >> Nitrenium ion formation OR SN1 >> Nitrenium ion formation >> Aminoacridine Derivatives OR SN1 >> Nitrenium ion formation >> Aromatic and Heterocyclic Primary Amines OR SN1 >> Nitrenium ion formation >> N-hydroxylamines OR SN1 >> Nitrenium ion formation >> Nitro Compounds OR SN1 >> Nitrenium ion formation >> Sulfonyl Azides OR SN1 >> Nitrosation OR SN1 >> Nitrosation >> Alkylnitrites OR SN1 >> Non-enzymatic nitroso radical and/or nirtosonium cation formation OR SN1 >> Non-enzymatic nitroso radical and/or nirtosonium cation formation >> Nitroso compounds OR SN1 >> Non-enzymatic nitroso radical and/or nirtosonium cation formation >> Urea Derivatives OR SN2 OR SN2 >> Acylating agents OR SN2 >> Acylating agents >> Specific Acetate Esters OR SN2 >> Carbenium Ion Formation OR SN2 >> Carbenium Ion Formation >> Acyclic Triazenes OR SN2 >> Carbenium Ion Formation >> Arenediazonium Salts OR SN2 >> Carbenium Ion Formation >> Diazoalkanes OR SN2 >> Diazonium ion formation OR SN2 >> Diazonium ion formation >> Specific Imine and Thione Derivatives OR SN2 >> Direct acting aziridines OR SN2 >> Direct acting aziridines >> Aminoacridine Derivatives OR SN2 >> Direct Acting Epoxides and Related OR SN2 >> Direct Acting Epoxides and Related >> Epoxides, Aziridines OR SN2 >> Direct Acting Epoxides and Related >> Nitrogen Mustards OR SN2 >> Direct acylation involving a leaving group OR SN2 >> Direct acylation involving a leaving group >> Acyl Halides OR SN2 >> Epoxidation of Aliphatic Alkenes OR SN2 >> Epoxidation of Aliphatic Alkenes >> Polarized Haloalkene Derivatives OR SN2 >> Internal SN2 reaction with aziridinium and/or cyclic sulfonic ion formation OR SN2 >> Internal SN2 reaction with aziridinium and/or cyclic sulfonic ion formation >> Vicinal Dihaloalkanes OR SN2 >> Nucleophilic substitution at sp3 Carbon atom OR SN2 >> Nucleophilic substitution at sp3 Carbon atom >> Geminal Polyhaloalkanes OR SN2 >> Nucleophilic substitution at sp3 Carbon atom >> Haloalkanes Containing Electron-Withdrawing Groups OR SN2 >> Nucleophilic substitution at sp3 Carbon atom >> Haloalkanes Containing Heteroatom OR SN2 >> P450-mediated epoxidation OR SN2 >> P450-mediated epoxidation >> Coumarins OR SN2 >> P450-mediated epoxidation >> Polarized Haloalkene Derivatives OR SN2 >> P450-mediated epoxidation >> Polycyclic Aromatic Hydrocarbons OR SN2 >> Ring opening SN2 reaction OR SN2 >> Ring opening SN2 reaction >> Four- and Five-Membered Lactones OR SN2 >> SN2 at Nitrogen Atom OR SN2 >> SN2 at Nitrogen Atom >> N-acetoxyamines OR SN2 >> SN2 at sp3 and activated sp2 carbon atom OR SN2 >> SN2 at sp3 and activated sp2 carbon atom >> Polarized Haloalkene Derivatives OR SN2 >> SN2 at sp3-carbon atom OR SN2 >> SN2 at sp3-carbon atom >> Alkylphosphates, Alkylthiophosphates and Alkylphosphonates OR SN2 >> SN2 at sp3-carbon atom >> Alpha-Haloethers OR SN2 >> SN2 at sp3-carbon atom >> Specific Acetate Esters OR SN2 >> SN2 at sp3-carbon atom >> Sulfonates and Sulfates OR SN2 >> SN2 at sulfur atom OR SN2 >> SN2 at sulfur atom >> Sulfonyl Halides by DNA binding by OASIS v.1.1

Domain logical expression index: "g"

Referential boundary: The target chemical should be classified as Alkoxy AND Aryl AND Ether by Organic functional groups

Domain logical expression index: "h"

Referential boundary: The target chemical should be classified as Alkoxy AND Aryl AND Ether AND Overlapping groups by Organic functional groups (nested)

Domain logical expression index: "i"

Referential boundary: The target chemical should be classified as Aliphatic Carbon [CH] AND Aliphatic Carbon [-CH2-] AND Aliphatic Carbon [-CH3] AND Aromatic Carbon [C] AND Olefinic carbon [=CH- or =C<] AND Oxygen, one aromatic attach [-O-] by Organic functional groups (US EPA)

Domain logical expression index: "j"

Referential boundary: The target chemical should be classified as Alkylarylether AND Aromatic compound AND Ether by Organic functional groups, Norbert Haider (checkmol)

Domain logical expression index: "k"

Referential boundary: The target chemical should be classified as Non binder, without OH or NH2 group by Estrogen Receptor Binding

Domain logical expression index: "l"

Referential boundary: The target chemical should be classified as Moderate binder, NH2 group OR Moderate binder, OH grooup OR Non binder, impaired OH or NH2 group OR Non binder, MW>500 OR Non binder, non cyclic structure OR Strong binder, NH2 group OR Strong binder, OH group OR Weak binder, NH2 group OR Weak binder, OH group OR Very strong binder, OH group by Estrogen Receptor Binding

Domain logical expression index: "m"

Referential boundary: The target chemical should be classified as Alkoxy AND Aryl AND Ether by Organic functional groups

Domain logical expression index: "n"

Referential boundary: The target chemical should be classified as Alkoxy AND Aryl AND Ether AND Overlapping groups by Organic functional groups (nested)

Domain logical expression index: "o"

Referential boundary: The target chemical should be classified as Aliphatic Carbon [CH] AND Aliphatic Carbon [-CH2-] AND Aliphatic Carbon [-CH3] AND Aromatic Carbon [C] AND Olefinic carbon [=CH- or =C<] AND Oxygen, one aromatic attach [-O-] by Organic functional groups (US EPA)

Domain logical expression index: "p"

Referential boundary: The target chemical should be classified as Alkylarylether AND Aromatic compound AND Ether by Organic functional groups, Norbert Haider (checkmol)

Domain logical expression index: "q"

Referential boundary: The target chemical should be classified as No alert found by Protein binding by OASIS v1.1

Domain logical expression index: "r"

Referential boundary: The target chemical should be classified as Acylation OR Acylation >> Acyl transfer via nucleophilic addition reaction OR Acylation >> Acyl transfer via nucleophilic addition reaction >> Isocyanates and isothiocyanates OR Acylation >> Direct acylation involving a leaving group OR Acylation >> Direct acylation involving a leaving group >> Acid anhydrides OR Acylation >> Direct acylation involving a leaving group >> Acyl halide of carboxylic acids OR Acylation >> Direct acylation involving a leaving group >> Azalactones OR Acylation >> Direct acylation involving a leaving group >> Carbamates OR Acylation >> Direct acylation involving a leaving group >> N-acylamides OR Acylation >> Direct acylation involving a leaving group >> N-acylated heteroaromatic amines OR Acylation >> Direct acylation involving a leaving group >> N-acylsulphonamides OR Acylation >> Direct acylation involving a leaving group >> Omega-haloalkyl carboxylic acid esters OR Acylation >> Direct acylation involving a leaving group >> Sulphonyl azides OR Acylation >> Direct acylation involving a leaving group >> Sulphonyl halides OR Acylation >> Ester aminolysis OR Acylation >> Ester aminolysis >> Amides OR Acylation >> Ester aminolysis >> Dithiocarbamates OR Acylation >> Ester aminolysis >> Dithioesters OR Acylation >> Ester aminolysis or thiolysis OR Acylation >> Ester aminolysis or thiolysis >> Activated alkyl or aryl esters OR Acylation >> Ester aminolysis or thiolysis >> Diarylesters OR Acylation >> Ring opening acylation OR Acylation >> Ring opening acylation >> Active cyclic agents OR Ionic OR Ionic >> Electrostatic interaction of tetraalkylammonium ions with protein carboxylates OR Ionic >> Electrostatic interaction of tetraalkylammonium ions with protein carboxylates >> Tetraalkylammonium ions OR Michael addition OR Michael addition >> a,b-unsaturated carbonyl compounds OR Michael addition >> a,b-unsaturated carbonyl compounds >> a,b-unsatuarted aldehydes OR Michael addition >> Michael addition on conjugated systems with electron withdrawing group OR Michael addition >> Michael addition on conjugated systems with electron withdrawing group >> alpha,beta-carbonyl compounds with polarized double bonds OR Michael addition >> Michael addition on conjugated systems with electron withdrawing group >> Cyanoalkenes OR Michael addition >> Michael addition on conjugated systems with electron withdrawing group >> Nitroalkenes OR Michael addition >> Michael addition on conjugated systems with electron withdrawing group >> N-sulfonylazomethyne compounds OR Michael addition >> Michael addition on conjugated systems with electron withdrawing group >> Vinyl sulfonyl compounds OR Michael addition >> Michael type addition on vinyl pirydines and activated ethenylarenes OR Michael addition >> Michael type addition on vinyl pirydines and activated ethenylarenes >> Activated electrophilic ethenylarenes OR Michael addition >> Michael type addition on vinyl pirydines and activated ethenylarenes >> Vinyl pyridines OR Michael addition >> Michael-type addition on azoxy compounds OR Michael addition >> Michael-type addition on azoxy compounds >> Azoxy compounds OR Michael addition >> Quinone type compounds OR Michael addition >> Quinone type compounds >> Naphtoquinone and naphtoquinone imines OR Michael addition >> Quinone type compounds >> Quinone (di)imines OR Michael addition >> Quinone type compounds >> Quinone methides OR Michael addition >> Quinone type compounds >> Quinones OR Nucleophilic addition OR Nucleophilic addition >> Addition to Carbon-hetero double/triple bond OR Nucleophilic addition >> Addition to Carbon-hetero double/triple bond >> Ketones OR Nucleophilic addition >> Addition to Carbon-hetero double/triple bond >> Thiocyanates OR Nucleophilic addition >> Nucleophilic addition at polarized N-functional double bond OR Nucleophilic addition >> Nucleophilic addition at polarized N-functional double bond >> C-Nitroso compounds OR Nucleophilic addition >> Nucleophilic addition reaction across carbodiimide bond OR Nucleophilic addition >> Nucleophilic addition reaction across carbodiimide bond >> Carbodiimides OR Radical OR Radical >> Free radical formation OR Radical >> Free radical formation >> Organic peroxy compounds OR Schiff base formation OR Schiff base formation >> Nucleophilic cycloaddition to diketones OR Schiff base formation >> Nucleophilic cycloaddition to diketones >> Diketones OR Schiff base formation >> Pyrazolones and pyrazolidinones derivatives OR Schiff base formation >> Pyrazolones and pyrazolidinones derivatives >> Pyrazolones and pyrazolidinones OR Schiff base formation >> Schiff base formation with carbonyl compounds OR Schiff base formation >> Schiff base formation with carbonyl compounds >> Aldehydes OR SN1 OR SN1 >> Carbenium ion formation OR SN1 >> Carbenium ion formation >> Azoxy compounds-forming carbenium ion OR SN1 >> Nucleophilic substitution (SN1) on alkyl (aryl) mercury cations OR SN1 >> Nucleophilic substitution (SN1) on alkyl (aryl) mercury cations >> Mercury compounds OR SN2 OR SN2 >> Interchange reaction with sulphur containing compounds OR SN2 >> Interchange reaction with sulphur containing compounds >> Thiols and disulfide compounds OR SN2 >> Nucleophilic substitution at Nitrogen atom OR SN2 >> Nucleophilic substitution at Nitrogen atom >> N-nitroso compounds OR SN2 >> Nucleophilic substitution at Nitrogen atom >> N-oxicarbonyl amides OR SN2 >> Nucleophilic substitution at sp3 Carbon atom OR SN2 >> Nucleophilic substitution at sp3 Carbon atom >> Activated alkyl esters OR SN2 >> Nucleophilic substitution at sp3 Carbon atom >> alpha-activated haloalkanes OR SN2 >> Nucleophilic substitution at sp3 Carbon atom >> alpha-haloalkanes OR SN2 >> Nucleophilic substitution at sp3 Carbon atom >> N-nitroso compounds OR SN2 >> Nucleophilic substitution at sp3 Carbon atom >> Phosphates OR SN2 >> Nucleophilic substitution at sp3 Carbon atom >> Phosphonates OR SN2 >> Nucleophilic substitution at sp3 Carbon atom >> Sulfonates OR SN2 >> Nucleophilic substitution at sp3 Carbon atom >> Thiophosphates OR SN2 >> Nucleophilic substitution on benzylic carbon atom OR SN2 >> Nucleophilic substitution on benzylic carbon atom >> alpha-activated benzyls OR SN2 >> Nucleophilic substitution on benzylic carbon atom >> Benzylic esters OR SN2 >> Nucleophilic substitution on heterocyclic sulfenamides OR SN2 >> Nucleophilic substitution on heterocyclic sulfenamides >> Heterocyclic sulfenamides OR SN2 >> Nucleophilic substitution to the central carbon atom of N-nitroso compounds OR SN2 >> Nucleophilic substitution to the central carbon atom of N-nitroso compounds >> N-nitroso compouns excluding aromatic OR SN2 >> Ring opening SN2 reaction OR SN2 >> Ring opening SN2 reaction >> Epoxides, Aziridines and Sulfuranes OR SN2 >> Ring opening SN2 reaction >> Isothiazolones derivatives OR SN2 Ionic OR SN2 Ionic >> Nucleophilic substitution at sulfur atom in disulfides OR SN2 Ionic >> Nucleophilic substitution at sulfur atom in disulfides >> Arenesulfinic acids OR SNAr OR SNAr >> Nucleophilic aromatic substitution on activated halogens OR SNAr >> Nucleophilic aromatic substitution on activated halogens >> Activated haloarenes by Protein binding by OASIS v1.1

Domain logical expression index: "s"

Referential boundary: The target chemical should be classified as Bioavailable by Lipinski Rule Oasis

Domain logical expression index: "t"

Referential boundary: The target chemical should be classified as Not bioavailable by Lipinski Rule Oasis



Metabolism boundary:Metabolism simulator:Observed Rat In vivo metabolism

Domain logical expression index: "u"

Parametric boundary:The target chemical should have a value of log Kow which is >= 1.1

Domain logical expression index: "v"

Parametric boundary:The target chemical should have a value of log Kow which is <= 2.62

Conclusions:

The reproductive toxicity NOAEL (No observed Adverse effect level) of phenetole in rat is predicted at a dose concentration of 1360 mg/kg bw/day.This indicates that phenetole shall not exhibit toxic effect to mouse below the above mention dose.

Executive summary:

The NOAEL for phenetole is estimated to be 1360 mg/kg bw/day for rat for 8 weeks using the toolbox version 3.2. The data is estimated to be based on the data summarized below

 

CAS no.	End point	Value	Species	Doses	Duration	Effects	Remarks
104-93-8	NOAEL(general systemic toxicity, Fertility, Developmental toxicity)	>= 1000 mg/kg bw/day	Rat Wistar	100, 300, 1000 mg/kg bw/d	8 weeks	No test substance related adverse effects observed.	Parameters-clinical signs; mortality; body weight, food consumption Litter observation-number and sex of pups (Sex ratio), stillbirths, live births, postnatal mortality, presence of gross anomalies, clinical symptoms, body weights Gross and histopathology,Reproductive indices and viability index.
	NOAEL (general systemic toxicity, Fertility, Developmental toxicity)	100 mg/kg bw/day	Rat Wistar	100, 300, 1000 mg/kg bw/d	8 weeks	No test substance related adverse effects observed.	Overall effects as above
770-35-4	NOAEL	500 ppm(477.5 mg/kg body weight/day (mean dose)	Rat Wistar	100 ppm(11.3 mg/kg body weight/day (mean dose)), 1000 ppm(113.9 mg/kg body weight/day (mean dose), 5000 ppm(477.5 mg/kg body weight/day (mean dose)	40 weeks	No effects	Based on reproductive performance and fertility
	NOAEL(Develomental and general systemic toxicity)	1000 ppm (113.9 mg/kg body weight/day)	Same as above	Same as above	Same as a above	No effects	Pathology and histopathology did not reveal substance-related adverse effects
122-99-6	LOAEL reproductive effects(Male)	> 3700 mg/kg bw/day	Mouse CD 1	0, 0.25, 1.25, 2.5 %(These concentrations produced calculated consumption estimates of nearly equal to 375, 1875, and 3700 mg/kg/day).	126 days	Based on the absence of effects on male fertility
	LOAEL reproductive effects(Female)	1875 mg/kg bw/day	Same as above	Same as above	Same as above	Based on reduced offspring body weight
	NOAEL reproductive effects(male)	ca. 3700 mg/kg bw/day	Same as above	Same as above	Same as above	No effects on sperm measures and test substance intake
	NOAEL reproductive effects(Female)	ca. 1875 mg/kg bw/day	Same as above	Same as above	Same as above	No effects on estrous cyclicity.

 

Based on the above values it is concluded  that estimated value 1360 mg/kg bw/day of the target substance phenetole is more close to NOAEL value of readacross CAS 104-93-8 that is >= 1000 mg/kg bw/day. Considering the proximity between the two values it is assessed that the predicted value 1360 mg/kg bw/day of target is an NOAEL value. On the basis of this assessement it is concluded that the reproductive toxicity NOAEL value of phenetole in wistar rat via dermal route for a duration of 8 weeks is predicted to be 1360 mg/kg bw/day.

Reference 2

Endpoint:

one-generation reproductive toxicity

Remarks:

based on test type (migrated information)

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Qualifier:

according to guideline

Guideline:

other:

Principles of method if other than guideline:

Teratologic evaluation of 2-phenoxyethanol in New Zealand White rabbits following dermal exposure

GLP compliance:

not specified

Limit test:

no

Species:

rabbit

Strain:

New Zealand White

Sex:

male/female

Details on test animals or test system and environmental conditions:

Details on test animal & Environmental conditions
TEST ANIMALS
- Source: Hazelton-Dutch land, Denver, PA.
- Weight at study initiation: approx. 3.5-4.5 kg bodyweight
- Housing: wire bottom cage
- Diet (e.g. ad libitum): Certified Laboratory Rabbit Chow,
- Water (e.g. ad libitum): Tap water
- Acclimation period: Two weeks

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 deg C
- Humidity (%): 50 %(Relative humidity)
- Photoperiod (hrs dark / hrs light): 12 hours light and day.

Route of administration:

dermal

Vehicle:

unchanged (no vehicle)

Details on exposure:

The back of each rabbit was clipped with electric clippers. Test material was applied to the clipped area daily, Beginning on Day 6 of gestation. The application site was occluded using a piece of absorbent gauze and nonabsorbent cotton covered by a cotton flannel bandage held in place with tape. The bandages remained in place 24 hr a day throughout the treatment period (Days 6 through 18 of gestation). Prior to each application of test material, the skin at the application site was examined for signs of irritation and regrowth of hair. Bandages were replaced and the application site clipped as needed during the treatment period. On Day 19 of gestation, the bandages were removed and the application site washed with water.

Details on mating procedure:

Details of mating
The females were artifically insiminated
- Proof of pregnancy: the day of artificial insemination considered as Day 0 of gestation.

Duration of treatment / exposure:

13 days (day 6 through 18 of pregnancy)

Frequency of treatment:

Daily

Details on study schedule:

Female rabbits, approximately 3.5 to 4.5 kg, were artificially inseminated (Gibson et al., 1966), with the day of artificial insemination
considered as Day 0 of gestation.

Remarks:

Doses / Concentrations:
0, 300, 600, or 1000 mg/kg/day
Basis:
nominal conc.

No. of animals per sex per dose:

25 females in each group

Control animals:

yes, concurrent vehicle

Details on study design:

Groups of 25 inseminated rabbits were treated with 300, 600, or 1000 mg/kg/day of undiluted 2-pheno xyethanol, applied dermally, on Days 6 through 18 of gestation. The dose volume of undiluted 2-pheno xyethanol (sp gr = 1.1) was 0.27,0.55, and 0.91 ml/kg for the 300, 600, and 1000 mg/kg/day dose levels, respectively. Selection of dose levels was based on results of a previous study in which groups of 10 animals were treated with 0, 300, 600, or 1000 mg/kg/day of 2-phenoxyethanol on Days 6 through 18 of gestation. Minimal maternal toxicity as evidenced by a lower body weight gain on Days 15 through 18 of gestation was seen at 1000 mg/kg/day. The highest dose level of 1000 mg/kg/day was chosen due to the physical constraints, i.e., application of a liquid to a finite area of the animal's back without
excessive runoff at the time of application or subsequent loss into the occluding bandage. Control animals were treated with distilled water at a dose volume of 0.91 ml/kg body wt.

Parental animals: Observations and examinations:

Maternal body weights were recorded on gestation Days 6 through 19 and on Day 28.
Blood was collected from an ear vein from approximately 10 animals per dose group (0, 300, and 600 mg/kg/day) on Day 19 of gestation, and 3 animals (2 at 600 and 1 at 1000 mg/kg/day) sacrificed in extremis for the following measurements: packed cell volume (PCV), hemoglobin (Hgb), erythrocyte
count (RBC), total leukocyte count (WBC), red blood cell indices (MCV, MCH, MCHC), platelet count
(PLAT),6 reticulocyte count (Brecher and Schneiderman, 1950), osmotic red cell fragility (Schalm, 1968),
and WBC differential counts.

Litter observations:

All fetuses were weighed, measured (crown rump length), sexed, and examined for external alterations.

Postmortem examinations (parental animals):

Urine was collected at the time of necropsy from the bladders of two moribund rabbits (one each at 600 and 1000 mg/kg/day) via aspiration for urinalysis (color, appearance, specific gravity, pH, protein, glucose, ketones, bilirubin, blood, urobilinogen, white blood cells, red blood cells, and microscopic examination for crystals and epithelial cells).
Maternal liver weights were recorded at the time of cesarean section on Day 28 of gestation.
The uterine horns were exteriorized through a midline incision in the abdominal wall following carbon dioxide euthanasia, and the number of corpora lutea and the number and position of implantations, resorptions, and live or dead fetuses were recorded. The uteri of apparently nonpregnant animals were stained with a 10% solution of sodium sulfide (Kopf et al., 1964) and examined
for evidence of early implantation sites.

Postmortem examinations (offspring):

One-half of each litter, selected using a table of random numbers (Steel and Torrie, 1960), were examined under a dissecting stereomicroscope for evidence of visceral alterations (Staples, 1974). All fetuses were then preserved in 95% ethanol, cleared, stained with alizarin red S, and examined for skeletal alterations (Dawson, 1926).

Statistics:

Maternal and fetal body weights, absolute and relative organ weights, appropriate hematologic parameters, and fetal lengths were performed using a parametric or nonparametric analysis of variance followed by either a Dunnett's test or the Wilcoxon rank sum test with Bonferroni's correction (Steel and Torrie, I960; Winer, 1971; Hollander and Wolfe, 1973; Miller, 1966).
The frequency of pre implantation loss, resorptions among litters and the fetal population, and fetal alterations was performed by a censored Wilcoxon test (Haseman and Hoel, 1974) with Bonferroni's correction.
Corpora lutea, implants, and litter size were analyzed with a nonparametric analysis of variance followed by the Wilcoxon rank sum test with Bonferroni's correction. Pregnancy rates were analyzed by the Fisher's exact probability test (Siegel, 1956). Fetal sex ratios were analyzed by a binomial distribution test (Steel and Tome, 1960). The nominal level used for statistical evaluation was a = 0.05.

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

Subsequent to the onset of clinical signs, death followed rapidly, usually within a 24-hr period.

Body weight and weight changes:

no effects observed

Description (incidence and severity):

No differences in body weight gains or absolute weights were seen between control and treated rabbits

Food consumption and compound intake (if feeding study):

no effects observed

Description (incidence and severity):

No differences in body weight gains or absolute weights were seen between control and treated rabbits

Organ weight findings including organ / body weight ratios:

no effects observed

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

In moribund animals RBC counts and PCV values were severely depressed, whereas reticulocytes were elevated . In addition, red blood cell fragility was increased

Other effects:

not examined

Reproductive function: oestrous cycle:

not examined

Reproductive function: sperm measures:

not examined

Reproductive performance:

no effects observed

Description (incidence and severity):

No adverse effects on pregnancy rate, implantations resorbed, or fetal body measure ments were observed among rabbits dosed dermally with 300 or 600 mg/kg/day of 2- phenoxyethanol

Dose descriptor:

NOAEL

Effect level:

300 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

female

Basis for effect level:

other: Body weight,Organ weight,urinilysis, Histopathological examination

Remarks on result:

other: not specified

Critical effects observed:

not specified

System:

other: not specified

Organ:

not specified

Treatment related:

not specified

Dose response relationship:

not specified

Relevant for humans:

not specified

Clinical signs:

not examined

Mortality / viability:

no mortality observed

Body weight and weight changes:

no effects observed

Description (incidence and severity):

No adverse effects on body weight gain

Sexual maturation:

not examined

Organ weight findings including organ / body weight ratios:

not examined

Gross pathological findings:

not examined

Histopathological findings:

not examined

Other findings: the incidences of malformations observed externally, viscerally or at skeletal examination gave no indication of a teratogenic response at 2-phenoxyethanol levels up to 600 mg/kg/ day In the control group, single fetuses from different litters exhibited microphthalmia and anonychia. Single occurrences of hemivertebra and clinodactyly were observed among litters of dosed rabbits.

Remarks on result:

not measured/tested

Reproductive effects observed:

not specified

Treatment related:

not specified

Relation to other toxic effects:

not specified

Dose response relationship:

not specified

Relevant for humans:

not specified

Conclusions:

The No Observed Adverse Effect Level (NOAEL)of 2-penoxyethanol on female New zealand White Rabbit by dermal application was found to be 300 mg/kg/day

Executive summary:

The purpose of this study was to evaluate the maximum tolerated dose level of 2-phenoxy ethanol in pregnant rabbits via dermal application. Undiluted 2-phenoxyethanol was applied to the backs of New Zealand White rabbits at dose levels of 0,300, 600 or 1000 mg/kg/day on days 6 through 18 of gestation.

There is no difference in body weight, organ weight were seen between control and treated rabbits. Rabbits in the two highest dose groups which survived until Day 28 of gestation

showed no evidence of treatment-related effects.

Examination of rabbit fetuses indicated that, at the dosages tested, 2-phenoxyethanol was not embryotoxic, fetotoxic, or teratogenic. Hence theNo Observed Adverse Effect Level (NOAEL) was considerd to be300 mg/kg/day.

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

1 360 mg/kg bw/day

Species:

rat

Quality of whole database:

K2 level data has been obtained from QSAR model considered by OECD.

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

300 mg/kg bw/day

Study duration:

subacute

Species:

rabbit

Quality of whole database:

K2 level publication data of readacross.

Additional information

Toxicity to reproduction:

Based on the various studies available with Klimish rating 2 for the read across substances for CAS 103-73-1 based on the category approach of organic functional group along with similar mechanistic approach and having structural similarities defined by QSAR toolbox. This data is combined with the prediction done using the QSAR toolbox for the target chemical based on similar category approach, the results is summarized as follows-

 

Sr. No	End point	Value	Species	Effects	Remarks
1.	NOAEL	1360 mg/kg bw/day	Rat	Parameters-clinical signs; mortality; body weight, food consumption Litter observation-number and sex of pups (Sex ratio), stillbirths, live births, postnatal mortality, presence of gross anomalies, clinical symptoms, body weights Gross and histopathology,Reproductive indices and viability index.	Predicted data
2.	NOAEL(P)	300 mg/kg bw/day	Rabbit	Body weight,Organ weight,urinilysis, Histopathological examination	Publication(RA-122-99-6)
3.	1.LOAEL(P)-Male 2.LOAEL(P)-Female 3.LOAEL(F1)-Female 4.NOAEL(F1)-Male/female 5.NOAEL(F2)- Male/female	1. 3700 mg/kg bw/day 2. 1875 mg/kg bw/day 3. 1875 mg/kg bw/day 4. 375 mg/kg bw/day (nominal) 5. 375 mg/kg bw/day (nominal)	Mouse	1. Based on the effects on male fertility 2. Based on reduced offspring body weight 3. based on reduced pup weight 4. No effects on any of the parameters examined. 5. No effects on any of the parameters examined.	NTP Study report(RA-122-99-6)

 

Based on the studies summarized in the above table it can be observed that NOAEL values is expected to be in the range 300 -1360 mg/kg bw/day as well as LOAEL value for readacross substance varies from 1875-3700 mg/kg bw/day.The predicted value is well within the range of NOAEL.The effects observed on these doses was listed as follows-

Reduced weight of offsprings.

Effects on male fertility

Pup weight reduced.

        

Thus based on above discussion it can be concluded that substance phenetole with CAS number 103-73-1 is expected to show the similar toxicological effect based on the effects observed on the other category members. Since the no effective dose value (NOAEL) is higher than 300 mg/kg bw/day ,thus based on this value it can be concluded that substance phenetole is considered to be not toxic to maternal toxicity as well as developmental toxicity for the above mentioned dose or below 1360 mg/kg bw/day. Also there is no known evidence of adverse effect on Human of CAS: 103-73-1 as well as estrogen receptor binding affinity does not indicates any mechanistic trigger as the substance is found to be a weak binder and would not raise any concern of CAS: 103-73-1 on toxicity to reproduction.

Short description of key information:

Study indicates that Phenetole shall not exhibit toxic effect to mouse and rabbit via oral and dermal route respectively.

Justification for selection of Effect on fertility via oral route:

The  reproductive toxicity NOAEL (No observed Adverse effect level) of phenetole in rat is predicted at a dose concentration of 1360 mg/kg bw/day.This indicates that phenetole shall not exhibit toxic effect to mouse below the above mention dose.

Justification for selection of Effect on fertility via dermal route:

The No Observed Adverse Effect Level (NOAEL)of 2-penoxyethanol on female New zealand White Rabbit by dermal application was found to be 300 mg/kg/day

Effects on developmental toxicity

Description of key information

The fetotoxicity LOEL (Lowest observed effect level)  of phenetole in rabbit by dermal exposure was predicted  at a dose concentration of 725  mg/kg bw/day.This indicates that phenetole shall not exhibit toxic effect to rabbit by the dermal route below the above mention dose. For the parental generation, NOAEL and LOAEL were considered to be 0.25 and 2.5% per day, respectively. For the F1 generation, NOAEL and LOAEL were considered to be 0.25 and 1.25% per day, respectively, when mice were exposed to EGMPE.

Link to relevant study records

Reference

Reference 1

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Qualifier:

according to guideline

Guideline:

other: Reproductive Assessment by Continuous Breeding (RACB); protocol devised by the NTP

GLP compliance:

not specified

Limit test:

no

Species:

mouse

Strain:

other: CD-1 [COBS (ICR)BR outbred albino]

Details on test animals or test system and environmental conditions:

TEST ANIMALS

- Source: Charles River Breeding laboratories Inc., NY
- Age at study initiation: 11 weeks of age at the start of the continuous breeding.
- Weight at study initiation: 26.0-26.7 g
- Diet (e.g. ad libitum): NIH-07 open formula ground rodent chow, ad libitum
- Water (e.g. ad libitum): Deionized/filtered water, ad libitum
- Housing: Animals were housed in solid bottom polypropylene or polycarbonate cages with stainless steel wire lids and Ab-Sorb-Dri cage litter in a controlled environment.
- Acclimatization period: 5 weeks

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 70+2°F
- Humidity (%): Monitored by electronic hygrothermographs but no data were available.
- Air changes (per hr): 12-14 times per hour
- Photoperiod (hrs dark / hrs light): 14-hrs light/10-hrs dark

Route of administration:

oral: feed

Vehicle:

other: NIH-07 open formula ground rodent chow

Details on exposure:

PREPARATION OF DOSING SOLUTIONS: Each dose of ethylene glycol monophenyl ether (EGMPE) was independently blended into a small amount of ground feed. This mixture was added to a preweighed portion of feed and mixed in a blender for 15 min. Concentrations were found to be within 96-105 % of target levels.

DIET PREPARATION
- Rate of preparation of diet (frequency): Weekly
- Mixing appropriate amounts with (Type of food): NIH-07 open formula ground rodent chow
- Storage temperature of food: Stored at -20°C prior to use.

VEHICLE
- Justification for use and choice of vehicle (if other than water): NIH-07 open formula ground rodent chow
- Concentration in vehicle:
Task 1 (range-finding study): 0, 1.0, 2.5, 5.0, 7.5 or 10.0% per day
Task 2 (main study): 0, 0.25, 1.25 or 2.5% per day
- Amount of vehicle (if gavage): No data available
- Lot/batch no. (if required): No data available
- Purity: No data available

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Confirmation of dose levels and certification of stability of the bulk chemical were performed.

Details on mating procedure:

- If cohoused:
- M/F ratio per cage:1:1
- Length of cohabitation:98 days
- After ... days of unsuccessful pairing replacement of first male by another male with proven fertility.No data available
- Further matings after two unsuccessful attempts: [no / yes (explain)]No data available
- Verification of same strain and source of both sexes: [yes / no (explain)]No data available
-After successful mating each pregnant female was caged (how):After the 98 days of cohabitation, each male and female were housed individually for a period of 20 days.
- Proof of pregnancy: [vaginal plug / sperm in vaginal smear] referred to as [day 0 / day 1] of pregnancy-No data available
- Any other deviations from standard protocol:Differing from the defined pre-mating treatment period laid out in OECD 416, the RACB protocol involves a 98-day continuous breeding period. Unlike the OECD protocol, copulation takes place among animals without appreciable pre-treatment.

Duration of treatment / exposure:

7 days prior to and during a 98-day cohabitation period

Frequency of treatment:

Oral feed:in food, offered ad libitum

Duration of test:

126 days (7 days of prior to copulation and for 119 days mating trials)

Remarks:

Doses / Concentrations:
0, 1.0, 2.5, 5.0, 10.0 %
Basis:
other: nominal in diet range finder

Remarks:

Doses / Concentrations:
0, 0.25, 1.25, 2.5 %(These concentrations produced calculated consumption estimates of nearly equal to 375, 1875, and 3700 mg/kg/day).
Basis:
other: nominal in diet main study (concentrations selected on the basis of Task 1 (range finder)

No. of animals per sex per dose:

Task 1
Control: 8 males, 8 females
1.0% per day: 8 males, 8 females
2.5% per day: 8 males, 8 females
5.0% per day: 8 males, 8 females
7.5% per day: 8 males, 8 females
10.0% per day: 8 males, 8 females

Task 2
Control: 40 males, 40 females
0.25% per day: 20 males, 20 females
1.25% per day: 20 males, 20 females
2.5% per day: 20 males, 20 females

Control animals:

yes, concurrent vehicle

Details on study design:

Further details on study design
- Dose selection rationale: Task 1: A 14-day dose-range study (range finder) was performed.
- Rationale for animal assignment (if not random):No data available
- Other: No data available

Maternal examinations:

Mortality, body weight, body weight change, fertility and live pup.

Ovaries and uterine content:

Examined

Fetal examinations:

Number of live pups, live pups per litter, live pup weight and sex.

Statistics:

A two-way analysis of variance (dose x sex) and percent mortality will be analyzed by the Chi Square Test. A Kruskal-Wallis analysis of variance on ranks was employed to compare the number of litters per breeding pair among treatment groups. If this test shows significant differences among treatment groups, the Mann-Whitney U Test was used to make intergroup pairwise comparisons. A Chi Square Test was utilized to determine significant differences in the number and percent fertile pairs among treatment groups. The total number of newborn produced by a pair, and the overall mean body weight of live pups per pair, was analyzed by a one-way ANOVA. An arcsine square-root transformation was performed on the percent live newborn per pair. The transformed data was then analyzed by a one-way ANOVA. If the ANOVA showed a significant difference among treatment groups, a Duncan's Multiple Range Test was utilized to make intergroup pairwise comparisons.

Indices:

Fertility index

Historical control data:

No data available

Details on maternal toxic effects:

Maternal toxic effects:yes

Details on maternal toxic effects:
Task 1
During the 14-days exposure 2 males and 3 females exhibited dehydration in the 7.5 % per day dose group, however, one of the females in the 7.5 % per day dose group died before conclusion of task 1. Three of 7 males and 2 of 4 females in the 10 % per day group that exhibited dehydration and pilo-erection during the first week died during the second week. By statistical analysis, the percent lethality was significantly elevated in the 10 % per day dose group. In addition, the % weight gain for the sexes combined was significantly decreased in the 5 % per day group relative to the lower dose and control group.

Task 2
Continuous exposure of CD-1 mice to the dietary levels had no effect on the number of pairs able to produce at least one litter. No effect on the sex (males/total) of pups born alive was observed. In contrast, exposure to 2.5 % per day in the feed tended to reduce the number of litters delivered per pair and significantly reduced the average litter size and proportion of pups born alive compared to the control and the 0.25 % and 1.25 % per day groups. Further there was a significant dose-related decrease in live pup weight during continuous exposure of F0 breeding pairs. Live pup weight adjusted for total pups per litter showed a similar dose-related pattern.

Dose descriptor:

LOAEL

Remarks:

Male/Female

Effect level:

> 3 700 - 4 375 mg/kg bw/day (nominal)

Based on:

test mat.

Basis for effect level:

other: maternal toxicity

Remarks on result:

other: not specified

Dose descriptor:

LOAEL

Remarks:

Male/female

Effect level:

ca. 1 875 mg/kg bw/day (nominal)

Based on:

test mat.

Basis for effect level:

other: developmental toxicity

Remarks on result:

other: not specified

Dose descriptor:

NOAEL

Remarks:

Male/female

Effect level:

ca. 1 875 mg/kg bw/day (nominal)

Based on:

test mat.

Basis for effect level:

other: maternal toxicity

Remarks on result:

other: not specified

Dose descriptor:

NOAEL

Remarks:

male/female

Effect level:

ca. 375 mg/kg bw/day (nominal)

Based on:

test mat.

Basis for effect level:

other: developmental toxicity

Remarks on result:

other: not specified

Abnormalities:

not specified

Localisation:

not specified

Description (incidence and severity):

not specified

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:yes

Details on embryotoxic / teratogenic effects:
Further studies conducted in the current experiment showed evidence of reduced body weight gain to weaning and reduced organ weight, indicating EGMPE toxicity during the lactational and postweaning periods.

Dose descriptor:

other: not specified

Based on:

not specified

Sex:

not specified

Basis for effect level:

other: not specified

Remarks on result:

other: not specified

Abnormalities:

not specified

Localisation:

other: not specified

Description (incidence and severity):

not specified

Developmental effects observed:

not specified

Treatment related:

not specified

Relation to maternal toxicity:

not specified

Dose response relationship:

not specified

Relevant for humans:

not specified

Conclusions:

For the parental generation, NOAEL and LOAEL were considered to be 1.25 and 2.5% per day, respectively. For the F1 generation, NOAEL and LOAEL were considered to be 0.25 and 1.25% per day, respectively, when mice were exposed to EGMPE.

Executive summary:

In a reproductive and fertility assessment toxicity study, the effect of ethylene glycol monophenyl ether (EGMPE) was evaluated in CD-1 mice. EGMPE was administered orally in feed at a different concentrations depending on the experimental task (Task 1: 0, 1.0, 2.5, 5.0, 7.5 or 10.0% per day; or Task 2: 0, 0.25, 1.25 or 2.5% per day). The results show that EGMPE caused significant toxicity in growing animals, as evidenced by the reduced body weight in neonates in Task 2, and a large increased post-natal lethality as the F1 animals grew to the age of mating. However, at lower treatment doses no adverse effects were observed. Therefore, when CD-1 mice were exposed to EGMPE by diet, NOAEL and LOAEL were considered to be 1.25%( ca.1875 mg/kg bw/day (nominal)) and 2.5%( Task 1 -4375 mg/kg bw/day, Task 2-3700 mg/kg bw), respectively, in the parental generation, whereas NOAEL and LOAEL were considered to be 0.25 and 1.25%( 375 mg/kg bw/day and ca.1875 mg/kg bw/day (nominal) and per day, respectively, in the F1 generation.

Reference 2

Endpoint:

developmental toxicity

Type of information:

migrated information: read-across based on grouping of substances (category approach)

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Qualifier:

according to guideline

Guideline:

other: estimated data

Principles of method if other than guideline:

Prediction using category approach; QSAR Toolbox 3.1; Read Across; 5 nearest analogues; Log Kow as descriptor

GLP compliance:

no

Species:

rabbit

Strain:

New Zealand White

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Acclimation period: at least two weeks
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22
- Humidity (%): 54-80
- Photoperiod (hrs dark / hrs light): 12

Route of administration:

dermal

Vehicle:

unchanged (no vehicle)

Duration of treatment / exposure:

days 6-18 of gestation

Frequency of treatment:

once daily

Duration of test:

28 days

No. of animals per sex per dose:

25

Dose descriptor:

other: not specified

Based on:

not specified

Basis for effect level:

other: not specified

Remarks on result:

other: not specified

Abnormalities:

not specified

Localisation:

not specified

Description (incidence and severity):

not specified

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:yes

Details on embryotoxic / teratogenic effects:
Single occurrences of hemivertebrae and clinodactyly were observed among litters of dosed animals.

Dose descriptor:

LOAEL

Effect level:

725 mg/kg bw/day

Based on:

test mat.

Sex:

not specified

Basis for effect level:

other: fetotoxicity

Remarks on result:

other: not specified

Abnormalities:

not specified

Localisation:

other: not specified

Description (incidence and severity):

not specified

Developmental effects observed:

not specified

Treatment related:

not specified

Relation to maternal toxicity:

not specified

Dose response relationship:

not specified

Relevant for humans:

not specified

The prediction was based on dataset comprised from the following descriptors: LOEL,NOEL
Estimation method: Takes average value from the 5 nearest neighbours
Domain  logical expression:Result: In Domain

((((("a" or "b" or "c" or "d" )  and ("e" and ( not "f") )  )  and (("g" or "h" or "i" or "j" )  and ("k" and ( not "l") )  )  and (("m" or "n" or "o" or "p" )  and ("q" and ( not "r") )  )  )  and "s" )  and ("t" and "u" )  )

Domain logical expression index: "a"

Referential boundary: The target chemical should be classified as Alkoxy AND Aryl AND Ether by Organic functional groups

Domain logical expression index: "b"

Referential boundary: The target chemical should be classified as Alkoxy AND Aryl AND Ether AND Overlapping groups by Organic functional groups (nested)

Domain logical expression index: "c"

Referential boundary: The target chemical should be classified as Aliphatic Carbon [CH] AND Aliphatic Carbon [-CH2-] AND Aliphatic Carbon [-CH3] AND Aromatic Carbon [C] AND Olefinic carbon [=CH- or =C<] AND Oxygen, one aromatic attach [-O-] by Organic functional groups (US EPA)

Domain logical expression index: "d"

Referential boundary: The target chemical should be classified as Alkylarylether AND Aromatic compound AND Ether by Organic functional groups, Norbert Haider (checkmol)

Domain logical expression index: "e"

Referential boundary: The target chemical should be classified as No alert found by DNA binding by OASIS v.1.1

Domain logical expression index: "f"

Referential boundary: The target chemical should be classified as Acylation OR Acylation >> Direct acyation involving a leaving group OR Acylation >> Direct acyation involving a leaving group >> Geminal Polyhaloalkanes OR Elimination (E2) OR Elimination (E2) >> E2 elimination reaction with epoxide formation OR Elimination (E2) >> E2 elimination reaction with epoxide formation >> Haloalcohols OR Michael addition OR Michael addition >> alpha, beta-unsaturated carabonyl compounds OR Michael addition >> alpha, beta-unsaturated carabonyl compounds >> Alpha, Beta-Unsaturated Aldehydes OR Michael addition >> alpha, beta-unsaturated carabonyl compounds >> Four- and Five-Membered Lactones OR Michael addition >> Quinone type compounds OR Michael addition >> Quinone type compounds >> Quinoneimine Derivatives OR Michael addition >> Quinone type compounds >> Quinones OR Nucleophilic addition OR Nucleophilic addition >> Nucleophilic addition reaction with cycloisomerization OR Nucleophilic addition >> Nucleophilic addition reaction with cycloisomerization >> Hydrazine Derivatives OR Radical OR Radical >> Free radical formation OR Radical >> Free radical formation >> Arenediazonium Salts OR Radical >> Generation of reactive oxygen species OR Radical >> Generation of reactive oxygen species >> Coumarins OR Radical >> Generation of reactive oxygen species >> Thiols OR Radical >> Radical decomposition OR Radical >> Radical decomposition >> Alkylnitrites OR Radical >> Radical mechanism by ROS formation OR Radical >> Radical mechanism by ROS formation >> Diazenes OR Radical >> Radical mechanism by ROS formation >> Geminal Polyhaloalkanes OR Radical >> Radical mechanism by ROS formation >> Hydrazine Derivatives OR Radical >> Radical mechanism by ROS formation >> Nitro Compounds OR Radical >> Radical mechanism by ROS formation >> Nitroso compounds OR Radical >> Radical mechanism by ROS formation >> Organic Peroxy Compounds OR Radical >> Radical mechanism by ROS formation >> Quinones OR Radical >> Radical mechanism by ROS formation >> Specific Imine and Thione Derivatives OR Radical >> ROS formation after GSH depletion OR Radical >> ROS formation after GSH depletion >> Aromatic and Heterocyclic Primary Amines OR Radical >> ROS formation after GSH depletion >> Haloalcohols OR Radical >> ROS formation after GSH depletion >> Quinoneimine Derivatives OR Schiff base fomers OR Schiff base fomers >> Direct acting Schiff base formers OR Schiff base fomers >> Direct acting Schiff base formers >> Alkylnitrites OR Schiff base fomers >> Direct acting Schiff base formers >> Alpha, Beta-Unsaturated Aldehydes OR Schiff base fomers >> Direct acting Schiff base formers >> Geminal Polyhaloalkanes OR Schiff base fomers >> Direct acting Schiff base formers >> Specific Acetate Esters OR Schiff base fomers >> Multi-step Shiff base formation OR Schiff base fomers >> Multi-step Shiff base formation >> Haloalkanes Containing Electron-Withdrawing Groups OR SN1 OR SN1 >> Carbenium ion formation OR SN1 >> Carbenium ion formation >> Alpha-Haloethers OR SN1 >> Carbenium ion formation >> Nitroso compounds OR SN1 >> Carbenium ion formation >> Polycyclic Aromatic Hydrocarbons OR SN1 >> Carbenium ion formation >> Specific Acetate Esters OR SN1 >> Glutathione-induced nitrenium ion formation OR SN1 >> Glutathione-induced nitrenium ion formation >> Nitroso compounds OR SN1 >> Nitrenium and/or Carbenium ion formation OR SN1 >> Nitrenium and/or Carbenium ion formation >> Urea Derivatives OR SN1 >> Nitrenium ion and/or Acyl ion formation OR SN1 >> Nitrenium ion and/or Acyl ion formation >> N-acyloxy-N-alkoxyamides OR SN1 >> Nitrenium ion formation OR SN1 >> Nitrenium ion formation >> Aminoacridine Derivatives OR SN1 >> Nitrenium ion formation >> Aromatic and Heterocyclic Primary Amines OR SN1 >> Nitrenium ion formation >> N-hydroxylamines OR SN1 >> Nitrenium ion formation >> Nitro Compounds OR SN1 >> Nitrenium ion formation >> Sulfonyl Azides OR SN1 >> Nitrosation OR SN1 >> Nitrosation >> Alkylnitrites OR SN1 >> Non-enzymatic nitroso radical and/or nirtosonium cation formation OR SN1 >> Non-enzymatic nitroso radical and/or nirtosonium cation formation >> Nitroso compounds OR SN1 >> Non-enzymatic nitroso radical and/or nirtosonium cation formation >> Urea Derivatives OR SN2 OR SN2 >> Acylating agents OR SN2 >> Acylating agents >> Specific Acetate Esters OR SN2 >> Carbenium Ion Formation OR SN2 >> Carbenium Ion Formation >> Acyclic Triazenes OR SN2 >> Carbenium Ion Formation >> Arenediazonium Salts OR SN2 >> Carbenium Ion Formation >> Diazoalkanes OR SN2 >> Diazonium ion formation OR SN2 >> Diazonium ion formation >> Specific Imine and Thione Derivatives OR SN2 >> Direct acting aziridines OR SN2 >> Direct acting aziridines >> Aminoacridine Derivatives OR SN2 >> Direct Acting Epoxides and Related OR SN2 >> Direct Acting Epoxides and Related >> Epoxides, Aziridines OR SN2 >> Direct Acting Epoxides and Related >> Nitrogen Mustards OR SN2 >> Direct acylation involving a leaving group OR SN2 >> Direct acylation involving a leaving group >> Acyl Halides OR SN2 >> Epoxidation of Aliphatic Alkenes OR SN2 >> Epoxidation of Aliphatic Alkenes >> Polarized Haloalkene Derivatives OR SN2 >> Internal SN2 reaction with aziridinium and/or cyclic sulfonic ion formation OR SN2 >> Internal SN2 reaction with aziridinium and/or cyclic sulfonic ion formation >> Vicinal Dihaloalkanes OR SN2 >> Nucleophilic substitution at sp3 Carbon atom OR SN2 >> Nucleophilic substitution at sp3 Carbon atom >> Geminal Polyhaloalkanes OR SN2 >> Nucleophilic substitution at sp3 Carbon atom >> Haloalkanes Containing Electron-Withdrawing Groups OR SN2 >> Nucleophilic substitution at sp3 Carbon atom >> Haloalkanes Containing Heteroatom OR SN2 >> P450-mediated epoxidation OR SN2 >> P450-mediated epoxidation >> Coumarins OR SN2 >> P450-mediated epoxidation >> Polarized Haloalkene Derivatives OR SN2 >> P450-mediated epoxidation >> Polycyclic Aromatic Hydrocarbons OR SN2 >> Ring opening SN2 reaction OR SN2 >> Ring opening SN2 reaction >> Four- and Five-Membered Lactones OR SN2 >> SN2 at Nitrogen Atom OR SN2 >> SN2 at Nitrogen Atom >> N-acetoxyamines OR SN2 >> SN2 at sp3 and activated sp2 carbon atom OR SN2 >> SN2 at sp3 and activated sp2 carbon atom >> Polarized Haloalkene Derivatives OR SN2 >> SN2 at sp3-carbon atom OR SN2 >> SN2 at sp3-carbon atom >> Alkylphosphates, Alkylthiophosphates and Alkylphosphonates OR SN2 >> SN2 at sp3-carbon atom >> Alpha-Haloethers OR SN2 >> SN2 at sp3-carbon atom >> Specific Acetate Esters OR SN2 >> SN2 at sp3-carbon atom >> Sulfonates and Sulfates OR SN2 >> SN2 at sulfur atom OR SN2 >> SN2 at sulfur atom >> Sulfonyl Halides by DNA binding by OASIS v.1.1

Domain logical expression index: "g"

Referential boundary: The target chemical should be classified as Alkoxy AND Aryl AND Ether by Organic functional groups

Domain logical expression index: "h"

Referential boundary: The target chemical should be classified as Alkoxy AND Aryl AND Ether AND Overlapping groups by Organic functional groups (nested)

Domain logical expression index: "i"

Referential boundary: The target chemical should be classified as Aliphatic Carbon [CH] AND Aliphatic Carbon [-CH2-] AND Aliphatic Carbon [-CH3] AND Aromatic Carbon [C] AND Olefinic carbon [=CH- or =C<] AND Oxygen, one aromatic attach [-O-] by Organic functional groups (US EPA)

Domain logical expression index: "j"

Referential boundary: The target chemical should be classified as Alkylarylether AND Aromatic compound AND Ether by Organic functional groups, Norbert Haider (checkmol)

Domain logical expression index: "k"

Referential boundary: The target chemical should be classified as Non binder, without OH or NH2 group by Estrogen Receptor Binding

Domain logical expression index: "l"

Referential boundary: The target chemical should be classified as Moderate binder, NH2 group OR Moderate binder, OH grooup OR Non binder, impaired OH or NH2 group OR Non binder, MW>500 OR Non binder, non cyclic structure OR Strong binder, NH2 group OR Strong binder, OH group OR Weak binder, NH2 group OR Weak binder, OH group OR Very strong binder, OH group by Estrogen Receptor Binding

Domain logical expression index: "m"

Referential boundary: The target chemical should be classified as Alkoxy AND Aryl AND Ether by Organic functional groups

Domain logical expression index: "n"

Referential boundary: The target chemical should be classified as Alkoxy AND Aryl AND Ether AND Overlapping groups by Organic functional groups (nested)

Domain logical expression index: "o"

Referential boundary: The target chemical should be classified as Aliphatic Carbon [CH] AND Aliphatic Carbon [-CH2-] AND Aliphatic Carbon [-CH3] AND Aromatic Carbon [C] AND Olefinic carbon [=CH- or =C<] AND Oxygen, one aromatic attach [-O-] by Organic functional groups (US EPA)

Domain logical expression index: "p"

Referential boundary: The target chemical should be classified as Alkylarylether AND Aromatic compound AND Ether by Organic functional groups, Norbert Haider (checkmol)

Domain logical expression index: "q"

Referential boundary: The target chemical should be classified as No alert found by Protein binding by OASIS v1.1

Domain logical expression index: "r"

Referential boundary: The target chemical should be classified as Acylation OR Acylation >> Acyl transfer via nucleophilic addition reaction OR Acylation >> Acyl transfer via nucleophilic addition reaction >> Isocyanates and isothiocyanates OR Acylation >> Direct acylation involving a leaving group OR Acylation >> Direct acylation involving a leaving group >> Acid anhydrides OR Acylation >> Direct acylation involving a leaving group >> Acyl halide of carboxylic acids OR Acylation >> Direct acylation involving a leaving group >> Azalactones OR Acylation >> Direct acylation involving a leaving group >> Carbamates OR Acylation >> Direct acylation involving a leaving group >> N-acylamides OR Acylation >> Direct acylation involving a leaving group >> N-acylated heteroaromatic amines OR Acylation >> Direct acylation involving a leaving group >> N-acylsulphonamides OR Acylation >> Direct acylation involving a leaving group >> Omega-haloalkyl carboxylic acid esters OR Acylation >> Direct acylation involving a leaving group >> Sulphonyl azides OR Acylation >> Direct acylation involving a leaving group >> Sulphonyl halides OR Acylation >> Ester aminolysis OR Acylation >> Ester aminolysis >> Amides OR Acylation >> Ester aminolysis >> Dithiocarbamates OR Acylation >> Ester aminolysis >> Dithioesters OR Acylation >> Ester aminolysis or thiolysis OR Acylation >> Ester aminolysis or thiolysis >> Activated alkyl or aryl esters OR Acylation >> Ester aminolysis or thiolysis >> Diarylesters OR Acylation >> Ring opening acylation OR Acylation >> Ring opening acylation >> Active cyclic agents OR Ionic OR Ionic >> Electrostatic interaction of tetraalkylammonium ions with protein carboxylates OR Ionic >> Electrostatic interaction of tetraalkylammonium ions with protein carboxylates >> Tetraalkylammonium ions OR Michael addition OR Michael addition >> a,b-unsaturated carbonyl compounds OR Michael addition >> a,b-unsaturated carbonyl compounds >> a,b-unsatuarted aldehydes OR Michael addition >> Michael addition on conjugated systems with electron withdrawing group OR Michael addition >> Michael addition on conjugated systems with electron withdrawing group >> alpha,beta-carbonyl compounds with polarized double bonds OR Michael addition >> Michael addition on conjugated systems with electron withdrawing group >> Cyanoalkenes OR Michael addition >> Michael addition on conjugated systems with electron withdrawing group >> Nitroalkenes OR Michael addition >> Michael addition on conjugated systems with electron withdrawing group >> N-sulfonylazomethyne compounds OR Michael addition >> Michael addition on conjugated systems with electron withdrawing group >> Vinyl sulfonyl compounds OR Michael addition >> Michael type addition on vinyl pirydines and activated ethenylarenes OR Michael addition >> Michael type addition on vinyl pirydines and activated ethenylarenes >> Activated electrophilic ethenylarenes OR Michael addition >> Michael type addition on vinyl pirydines and activated ethenylarenes >> Vinyl pyridines OR Michael addition >> Michael-type addition on azoxy compounds OR Michael addition >> Michael-type addition on azoxy compounds >> Azoxy compounds OR Michael addition >> Quinone type compounds OR Michael addition >> Quinone type compounds >> Naphtoquinone and naphtoquinone imines OR Michael addition >> Quinone type compounds >> Quinone (di)imines OR Michael addition >> Quinone type compounds >> Quinone methides OR Michael addition >> Quinone type compounds >> Quinones OR Nucleophilic addition OR Nucleophilic addition >> Addition to Carbon-hetero double/triple bond OR Nucleophilic addition >> Addition to Carbon-hetero double/triple bond >> Ketones OR Nucleophilic addition >> Addition to Carbon-hetero double/triple bond >> Thiocyanates OR Nucleophilic addition >> Nucleophilic addition at polarized N-functional double bond OR Nucleophilic addition >> Nucleophilic addition at polarized N-functional double bond >> C-Nitroso compounds OR Nucleophilic addition >> Nucleophilic addition reaction across carbodiimide bond OR Nucleophilic addition >> Nucleophilic addition reaction across carbodiimide bond >> Carbodiimides OR Radical OR Radical >> Free radical formation OR Radical >> Free radical formation >> Organic peroxy compounds OR Schiff base formation OR Schiff base formation >> Nucleophilic cycloaddition to diketones OR Schiff base formation >> Nucleophilic cycloaddition to diketones >> Diketones OR Schiff base formation >> Pyrazolones and pyrazolidinones derivatives OR Schiff base formation >> Pyrazolones and pyrazolidinones derivatives >> Pyrazolones and pyrazolidinones OR Schiff base formation >> Schiff base formation with carbonyl compounds OR Schiff base formation >> Schiff base formation with carbonyl compounds >> Aldehydes OR SN1 OR SN1 >> Carbenium ion formation OR SN1 >> Carbenium ion formation >> Azoxy compounds-forming carbenium ion OR SN1 >> Nucleophilic substitution (SN1) on alkyl (aryl) mercury cations OR SN1 >> Nucleophilic substitution (SN1) on alkyl (aryl) mercury cations >> Mercury compounds OR SN2 OR SN2 >> Interchange reaction with sulphur containing compounds OR SN2 >> Interchange reaction with sulphur containing compounds >> Thiols and disulfide compounds OR SN2 >> Nucleophilic substitution at Nitrogen atom OR SN2 >> Nucleophilic substitution at Nitrogen atom >> N-nitroso compounds OR SN2 >> Nucleophilic substitution at Nitrogen atom >> N-oxicarbonyl amides OR SN2 >> Nucleophilic substitution at sp3 Carbon atom OR SN2 >> Nucleophilic substitution at sp3 Carbon atom >> Activated alkyl esters OR SN2 >> Nucleophilic substitution at sp3 Carbon atom >> alpha-activated haloalkanes OR SN2 >> Nucleophilic substitution at sp3 Carbon atom >> alpha-haloalkanes OR SN2 >> Nucleophilic substitution at sp3 Carbon atom >> N-nitroso compounds OR SN2 >> Nucleophilic substitution at sp3 Carbon atom >> Phosphates OR SN2 >> Nucleophilic substitution at sp3 Carbon atom >> Phosphonates OR SN2 >> Nucleophilic substitution at sp3 Carbon atom >> Sulfonates OR SN2 >> Nucleophilic substitution at sp3 Carbon atom >> Thiophosphates OR SN2 >> Nucleophilic substitution on benzylic carbon atom OR SN2 >> Nucleophilic substitution on benzylic carbon atom >> alpha-activated benzyls OR SN2 >> Nucleophilic substitution on benzylic carbon atom >> Benzylic esters OR SN2 >> Nucleophilic substitution on heterocyclic sulfenamides OR SN2 >> Nucleophilic substitution on heterocyclic sulfenamides >> Heterocyclic sulfenamides OR SN2 >> Nucleophilic substitution to the central carbon atom of N-nitroso compounds OR SN2 >> Nucleophilic substitution to the central carbon atom of N-nitroso compounds >> N-nitroso compouns excluding aromatic OR SN2 >> Ring opening SN2 reaction OR SN2 >> Ring opening SN2 reaction >> Epoxides, Aziridines and Sulfuranes OR SN2 >> Ring opening SN2 reaction >> Isothiazolones derivatives OR SN2 Ionic OR SN2 Ionic >> Nucleophilic substitution at sulfur atom in disulfides OR SN2 Ionic >> Nucleophilic substitution at sulfur atom in disulfides >> Arenesulfinic acids OR SNAr OR SNAr >> Nucleophilic aromatic substitution on activated halogens OR SNAr >> Nucleophilic aromatic substitution on activated halogens >> Activated haloarenes by Protein binding by OASIS v1.1

Domain logical expression index: "s"

Similarity boundary:Target: c1(OCC)ccccc1
Threshold=40%,
Dice(Atom centered fragments)

Domain logical expression index: "t"

Parametric boundary:The target chemical should have a value of log Kow which is >= 1.1

Domain logical expression index: "u"

Parametric boundary:The target chemical should have a value of log Kow which is <= 5.55

Conclusions:

The fetotoxicity LOAEL (Lowest observed Adverse effect level) of phenetole in rabbit by dermal exposure was predicted at a dose concentration of 725 mg/kg bw/day.This indicates that phenetole shall not exhibit toxic effect to rabbit by the dermal route below the above mention dose.

Executive summary:

The LOAEL for phenetole is estimated to be 725 mg/kg bw/day for rat for 28 days using the toolbox version 3.2. The data is estimated to be based on the data summarized below

 

CAS no.	End point	Value	Species	Doses	Duration	Effects	Remarks
122-99-6	LOAEL (embryotoxicity / teratogenicity)	> 600 mg/kg bw/day	Rabbit (New Zealand White)	300, 600, 1000 mg/kg bw/day	28 days	Low incidences of malformations.	Single occurrences of hemivertebrae and clinodactyly
	NOAEL(maternal toxicity)	ca. 300 mg/kg bw/day	Rabbit (New Zealand White)	300, 600, 1000 mg/kg bw/day	28 days	No effects on maternal toxicity	-
95737-68-1	LOEL	1000 mg/kg bw/day	Rattus norvegicus	Not available	Not available	Maternal pregnancy loss,fetotoxicity	-

Based on the above values it is concluded  that estimated value 725 mg/kg bw/day of the target substance phenetole is more close to NOAEL value of readacross CAS 122-99-6 that is >600 mg/kg bw/day. Considering the proximity between the two values it is assessed that the predicted value 725 mg/kg bw/day is an LOAEL value. On the basis of this assessement it is concluded that the developmental toxicity LOAEL value of phenetole in New Zealand White rabbit via dermal route for a duration of 28 days is predicted to be 725 mg/kg bw/day.

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

375 mg/kg bw/day

Study duration:

subchronic

Species:

mouse

Quality of whole database:

K2 Level study report of readacross.

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

adverse effect observed

725 mg/kg bw/day

Study duration:

subacute

Species:

rabbit

Quality of whole database:

K2 level data has been obtained from QSAR model considered by OECD.

Additional information

Developmental toxicity:

Based on the various studies available with Klimish rating 2 for the read across substances for CAS 103-73-1 based on the category approach of organic functional group along with similar mechanistic approach and having structural similarities defined by QSAR toolbox. This data is combined with the prediction done using the QSAR toolbox for the target chemical based on similar category approach, the results is summarized as follows-

Sr. No	End point	Value	Species	Route	Effects	Remarks
1.	LOEL(Fetotoxicity)	725 mg/kg bw/day	Rabbit	Dermal	Single occurrences of hemivertebrae and clinodactyly were observed among litters of dosed animals.	Predicted data
2.	-	-	Human	-	Non teratogenic(Negative)	DEPA
3.	NOAEL(Teratogenicity)	300 mg/kg bw/day (nominal)	New zealand White Rabbit	Dermal	No effects ob External, visceral, skeletal alterations.	Publication(RA-122-99-6)
4.	1.LOAEL-Female (Developmental toxicity) 2.NOAEL(Male/female)	1. 1875 mg/kg bw/day (nominal) 2. 375 mg/kg bw/day (nominal)	Mouse	Oral	1. based on reduced pup weight 2. No effects observed on any of the parameters examined Litter observation- number and sex of pups, live births, live pup weight.	NTP Study report (RA-122-99-6)

 

Based on the studies summarized in the above table with various routes it can be observed that a NOAEL value varies from 300-375 mg/kg bw/dayand the LOAEL values varies from725-1875 mg/kg bw/day considering predicted data of target and data of readacross.The effects observed on these doses was listed as follows

·        Effects observed on litters - occurrences of hemivertebrae and clinodactyly were observed among litters of dosed animals.

·        Reduced pup weight was seen.

Thus based on above discussion it can be concluded that substance phenetole with CAS number 103-73-1 is expected to show the similar toxicological effect based on the effects observed on the other category members. Since the no effective dose value (NOAEL) is higher than 300 mg/Kg bw/d thus based on this value it can be concluded that substance phenetole is considered to be not toxic to maternal toxicity as well as developmental effects for the above mentioned dose. Also there is no known evidence of adverse effect on Human of CAS: 103-73-1 as well as estrogen receptor binding affinity does not indicates any mechanistic trigger as the substance is found to be a weak binder and would not raise any concern of CAS: 103-73-1 on developmental toxicity.

Justification for selection of Effect on developmental toxicity: via oral route:

For the parental generation, NOAEL and LOAEL were considered to be 0.25 and 2.5% per day, respectively. For the F1 generation, NOAEL and LOAEL were considered to be 0.25 and 1.25% per day, respectively, when mice were exposed to EGMPE.

Justification for selection of Effect on developmental toxicity: via dermal route:

The fetotoxicity LOAEL (Lowest observed Adverse effect level)  of phenetole in rabbit by dermal exposure was predicted  at a dose concentration of 725  mg/kg bw/day.This indicates that phenetole shall not exhibit toxic effect to rabbit by the dermal route below the above mention dose.

Justification for classification or non-classification

The chemical Phenetole does not exhibit toxicity to the reproductive system within the doses mentioned in the study end points.